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7AES

Human carbonic anhydrase II in complex with 2,3,5,6-tetrafluoro-N-methyl-4-propylsulfanyl-benzenesulfonamide

Summary for 7AES
Entry DOI10.2210/pdb7aes/pdb
Descriptorcarbonic anhydrase 2, ZINC ION, 2,3,5,6-tetrakis(fluoranyl)-~{N}-methyl-4-propylsulfanyl-benzenesulfonamide, ... (7 entities in total)
Functional Keywordsdrug design, carbonic anhydrase, benzenesulfonamide, metal-binding, lyase-lyase inhibitor complex, lyase
Biological sourceHomo sapiens
Total number of polymer chains1
Total formula weight30076.18
Authors
Paketuryte, V.,Smirnov, A.,Manakova, E.,Grazulis, S. (deposition date: 2020-09-18, release date: 2021-09-01, Last modification date: 2024-01-31)
Primary citationBaronas, D.,Dudutiene, V.,Paketuryte, V.,Kairys, V.,Smirnov, A.,Juozapaitiene, V.,Vaskevicius, A.,Manakova, E.,Grazulis, S.,Zubriene, A.,Matulis, D.
Structure and mechanism of secondary sulfonamide binding to carbonic anhydrases.
Eur.Biophys.J., 50:993-1011, 2021
Cited by
PubMed Abstract: Zinc-containing metalloenzyme carbonic anhydrase (CA) binds primary sulfonamides with extremely high, up to picomolar, affinity by forming a coordination bond between the negatively charged amino group and the zinc ion and making hydrogen bonds and hydrophobic contacts with other parts of the inhibitor molecule. However, N-methyl-substituted, secondary or tertiary sulfonamides bind CA with much lower affinity. In search for an explanation for this diminished affinity, a series of secondary sulfonamides were synthesized and, together with analogous primary sulfonamides, the affinities for 12 recombinant catalytically active human CA isoforms were determined by the fluorescent thermal shift assay, stopped-flow assay of the inhibition of enzymatic activity and isothermal titration calorimetry. The binding profile of secondary sulfonamides as a function of pH showed the same U-shape dependence seen for primary sulfonamides. This dependence demonstrated that there were protein binding-linked protonation reactions that should be dissected for the estimation of the intrinsic binding constants to perform structure-thermodynamics analysis. X-ray crystallographic structures of secondary sulfonamides and computational modeling dissected the atomic contributions to the binding energetics. Secondary sulfonamides bind to carbonic anhydrases via coordination bond between the negatively charged nitrogen of alkylated amino group and Zn(II) in the active site of CA. The binding reaction is linked to deprotonation of the amino group and protonation of the Zn(II)-bound hydroxide. To perform the structure-thermodynamics analysis, contributions of these linked reactions must be subtracted to determine the intrinsic energetics. In this aspect, the secondary sulfonamides are similar to primary sulfonamides as CA inhibitors.
PubMed: 34328515
DOI: 10.1007/s00249-021-01561-1
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (1.4 Å)
Structure validation

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数据于2025-07-23公开中

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